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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« The Atlantic Monthly on Drug Pipelines | Main | Running Out of Decent Molecules to Patent? »

June 9, 2010

Raising Your HDL - Through the Brain?

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Posted by Derek

For a long time now, people have been searching for a way to raise HDL levels (the so-called "good cholesterol"). Statins will lower your LDL, while raising HDL just a pinch, but no one has a good, robust way to do it. (Niacin is probably the closest thing, but not everyone can take it). Many have tried, and failed, with Pfizer's CETP inhibitor torcetrapib being the most notably horrendous.

Now there's a completely new way to regulate HDL, and it comes from a direction you might not expect: the brain. A new paper in Nature Neuroscience demonstrates that melanocortin signaling, ghrelin and GLP-1 change HDL levels, through both altered cholesterol synthesis and uptake. Since these are involved in a number of ways in food intake and metabolism, it makes sense (in retrospect) that there would be a lipoprotein connection, but this does seem to be a dramatically direct one. (More and more, it appears that many metabolic processes that were thought to be more peripheral are under some sort of central control, actually). As the authors put it:

An integrated neuroendocrine control of food intake, body weight and glucose homeostasis, as well as cholesterol metabolism and cardiovascular lipid exposure, would connect all of the hallmarks of the metabolic syndrome. Therapies promoting the increase of HDL levels have been proposed for the prevention of atherosclerosis in humans. . . We speculate that modulation of neuroendocrine circuits may offer therapeutic opportunities to prevent cardiovascular disease.

Yes, indeed. It's not going to be easy, though. Ghrelin and GLP-1 have already been looked at for diabetes and obesity therapy, and they're tricky to deal with. Small-molecule ghrelin antagonists are known - as I should know - and there have been many reports of melanocortin receptor ligands as well. Of course, the question will be how many other things you might mess with at the same time, but it's going to be very interesting and worthwhile to unravel these.

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease | The Central Nervous System


COMMENTS

1. Sam on June 9, 2010 10:16 AM writes...

Or you can just eat a proper diet along with compensatory supplementation (particularly Vitamin D3 and magnesium).

And by proper diet I mean one that excludes transfats, high PUFA (specifically O-6), fructose, gluten grains and soy.

Permalink to Comment

2. Kent G. Budge on June 9, 2010 10:49 AM writes...

I suffer from low HDL, as well as Type 2 diabetes, and I undertook a regimen of exercising for at least 45 minutes a day, six days a week; reducing my weight to put my BMI near the midpoint of the healthy band; reducing total fat intake; increasing omega-3 intake; increasing soluble fiber intake; etc., etc.

At the end of three months, my HDL had gone down slightly.

It's not a simple problem, and it's remarkably resistant to lifestyle changes. Nacin is out because of its tendency to raise glucose levels. So I'm pretty much out of luck on raising my HDL. Fortunately, my overall lipid profile, which wasn't that bad to begin with (other than the unfavorable LDL/HDL ratio) has responded very well to pravistatin, and the LDL/HDL ratio is down quite a bit.

I would welcome something that would raise HDL. Assuming, of course, that low HDL is the disease and not just a symptom, which isn't entirely clear. Statins definitely improve the life expectancy of type 2 diabetics, but it's less definite that it's their effect on cholesterol that does it.

Permalink to Comment

3. Ken on June 9, 2010 11:13 AM writes...

aren't dalcetrapib and anacetrapib both in late stage trials? While torcetrapib was a high-profile failure, it's seems like there is still plenty of potential for CETP inhibitors.

Permalink to Comment

4. In Vivo Veritas on June 9, 2010 11:31 AM writes...

C'mon Derek - you must be slipping - you mentioned the cardiac and sexual aspects of MC4 activity and you go & leave out the tanning effects?

Tan, erect, and heart racing would seem to be a wonder drug for most american males.......

Permalink to Comment

5. Mark on June 9, 2010 11:39 AM writes...

I remember reading an article about the failure of torcetrapib where a cardiologist said "No big surprise". Apparently there are people who have a genetic defect that results in very high HDL levels, but their mortality rate from CV disease is actually higher than for people that don't have such high levels.

Once again, we have very little idea on how all the pieces fit together.

Mark

Permalink to Comment

6. Resveratrol Receptor on June 9, 2010 12:44 PM writes...

Do MC4R agonists really tan humans? I was aware of their anti-flaccidity effects. That's really terrific.

I've been pushing a breast enhancement/birth control prolactin receptor agonist/progesterone combo pill but for some reason no one is interested (frowny face).

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7. gippgig on June 9, 2010 2:43 PM writes...

Fish oil is worth a try (see "Dietary Supplements, Charted", March 17, 2010). In my case:
2004 41 HDL
started fish oil
2007 52
2009 64
2010 62
Of course, one case, with over 2 years between tests, proves absolutely nothing...

Permalink to Comment

8. In Vivo Veritas on June 10, 2010 7:43 AM writes...

Hey Resveratrol Receptor
A pilot Phase I clinical trial conducted on three males by the College of Medicine, Pharmacology Department, University of Arizona in Tucson, Arizona published in 1996 reported that, "Melanotan II (MC4 agonist) has tanning activity in humans given only 5 low doses every other day by subcutaneous injection." The side effects reported were mild nausea and a "stretching and yawning complex" that correlated with spontaneous penile erections.......

Permalink to Comment

9. Mark L on June 11, 2010 6:03 AM writes...

No, MC4 agonism does not cause tanning. Melanotan II is a non-selective agonist of melanocortin receptors. Its tanning effects can be attributed to agonism of MC1 (and its pro-erectile activity to agonism of MC4).

Permalink to Comment

10. Cynthia on June 11, 2010 4:29 PM writes...

It's all the "healthy" eating where people scrupulously avoid meat and saturated fat that produces low HDL. In fact, saturated fats will raise your HDL pretty dramatically. Ronald Krauss is even conducting a clinical trial on the subject, along with observing the changes in LDL size and composition, i.e., the change from proatherogenic small dense LDL to larger fluffy LDL. Perhaps it is all orchestrated through hormone signalling, but there are clear dietary effects, it's just that most people are practicing the wrong diet.

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11. Iván Castro on December 20, 2010 2:45 AM writes...

Hi Mr. Dereck, I am a Chilean student of medicine and his post seemed me interesting, because this finding could become a useful tool to regulate the levels of HDL. I would like to see studies about it.

Permalink to Comment

12. Bee Welson on January 7, 2013 4:23 PM writes...

I have been checking out a few of your articles and i must say pretty good stuff. I will make sure to bookmark your blog.

Permalink to Comment

13. Yasmin Salera on March 29, 2014 12:53 PM writes...

конкурса Евровизия предполагам е ясно на всички безплодно конкурсче без никакви музикални достойства, но селската масовка

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